2-substituted furan-3,4-dicarboxylic acids and their corresponding saturated analogues



Patented Aug. 14, 1945 UNITED STATES PATENT OFFICE 2-SUBSTITUTED FURAN-3A-DICARBOXYLIC ACIDS AND THEIR CORRESPONDING SAT- URATED ANALOGUES I Klaus Hofmann, Summit, N. 3.. assirnor to Oiba Pharmaceutical Products, Incorporated, Summit, N. J.. a corporation of New Jersey No Drawing. Application September 25, 1942, Serial No. 459,674

9 Claims.

This invention relates to a process of preparing ii-substituted furan-3,4-dicarboxylic acids and their corresponding saturated analogues of the general structure I or IA. According to the prescoon n'ooo door: I I! Pi c: o-con,).-n

coon n= 11 R'OOC coon' a'ooc coon CHFCH| ---o t-o-ccnora a iicrmrn i- H: \O/

11000 coon 11000 00011 50/ "-(C i)r- {30/ H (CHQPR While the 2-methy1-3,4-furan dicarboxylic acid is known. the prior art contains no 2-substituted-3,4-dicarboxylic acids wherein the 2- substituent is a relatively complicated side chain as compared with the relatively simple CH:- group, nor was it at all obvious that the compounds with the complex z-substituents could be successfully prepared.

It has now been found that a great number of 2-substituted furan-3,4-dicarboxylic acids can be prepared according to the above general procedure. Suitable starting materials are the 2-substituted furans of the general formula II wherein R stands for a carboxyl group or a group which can be transformed into a carboxyl group and :1: stands for the numbers 2, 3. 4 and more.

Among the groups which can be transformed to a carboxyl group the following ones may be mentioned: aliphatic and aromatic esters such as methyl, ethyl, propyl, phenyl, benzyl esters; aliphatic and aromatic amides such as amide, monoand dimethylamide. diethyl amide, piperidide, anilide, N-methylanilide; nitrile: hydroxyl: halogen; aldehyde and derivatives thereof such as acetal.

Esters of the acetyiene-dicarboxylic acid which may be used in the reaction are, for example methyl, ethyl, propyl, isopropyl, phenyl, benzyl esters.

For the partial reduction of the intermediate of the formula III the following catalysts may for example be used: metals of the platinum group such as platinum, palladium or others as such or on carriers, or nickel in the various forms used for such purpose. The catalytic reduction of the furan ring to the corresponding saturated comzo pounds may be carried out by applying well known be understood that the examples are given by way of illustration and not of limitation.

Example 1 1.2 g. of furyl-(2) -n-valeric acid ethyl ester were mixed with 980 mg. of acetylene-dicarboxylic acid-diethyl ester and the mixture was heated on the steam bath for 18 hours, after which time the mixture was taken up in 10cc. of ethyl acetate and was hydrogenated in the presence of palladium black until 1 molecule of hydrogen had been absorbed.

The catalyst was then separated from the solution and the ethyl acetate was evaporated in vacuum, leaving a viscous oil which was distilled in vacuum. The fraction boiling between 165- 168" C. at 0.01 mm. pressure was collected and represents the triethyl-ester of furan-3,4-dicarboxy- (2) -n-valeric acid. when the ester is treated with alkali the free tricarboxyllc acid is obtained. M. P. 188-189 C.

The tricarboxylic acid was suspended in water and enough 2N KOH was added to make the solution pink to henolphthalein. Raney nickel was added to the solution and it was hydrogenated at 2400 pounds and C. for 5 hours. The solution was then acidiiied to Congo red. was evanorated to dryness in vacuo and the organic material was extracted with ethyl acetate. The extracted acids were esterifled in the usual manner and the methyl ester was distilled and the tetrahydro-3,4-dicarb methoxy-hrran-(fl) -n-valeric acid-methyl ester was obtained.

Example 2 -sure corresponds to iuran-8,4-dicarboxy-ethyl- (2)-n-valeric acid. Baponiiication of this ester yields the tricarboxylic acid M. P. 188-189 0., identical with the acid as obtained in Example 1.

Emmple 3 A solution of 2.35 g. of iuryl-(2) -n-valeric acid piperidide and 1.42 g. of acetylene-dicarboxylic acld-dimethyl ester were boiled for 10 hours in 50 cc. of dry benzene. The benzene was then evaporated in vacuum and the viscous residue dissolved in 20 cc. of methanol and hydrogenated in the presence of Raney nickel catalyst until one molecule of hydrogen had been absorbed. The solution was then separated from the catalyst by filtration, concentrated to dryness and the residue was distilled in vs cuum. The distillate was dissolved in a mixture oi. 5 cc. of methanol and 3 cc. of 5/N aqueous KOH, and the solution was refluxed for 2 hours. The methanol was removed in vacuo and the residue was acidified to Congo red. The iuran- .4 dicarboxy (2) n -valerlc acid piperidide separated out, which melted after recrystallization at 181 C. This material was hydrolyzed by boiling it 6 hours with 50 cc. of a mixture of 50% glacial acetic acid and 50% concentrated hydrochloric acid.- The residue after evaporation oi the acetic acid hydrochloric acid mixture melted at 188-189 C. and was identical with the material obtained according to Examples 1 and 2. Y

s grams of 3,4-dicarbethoxy-i'uran-(2) -n-valeric acid piperidlde were dissolved in 40 cc. of ethyl alcohol and were hydrogenated in the presence of nickel on kieselguhr catalyst at 150 C. and 2500 pounds pressure. The catalyst was then removed by filtration and the 3,4-dicarbethoxy-tetrahydroiuran- (2) -n-valeric acid piperidide was distilled in vacuum.

Example 6 double bond, had been taken up. The solution .was then separated from the catalyst and was evaporated in vacuo. The residue was distilled in vacuo to decompose the complex and the distillate was dissolved in a mixture of 20 cc. of methanol and 20 cc. of 5N NaOE and kept at 20' C. for 48 hours. The methanol was then distilled off and the rem aqueous solution was acidacids of the formula assure for 2 hours. The 3.4-dicarboxy-iuryl-(2) -n-valeraldehyde was extracted with ether and was exidized with ireshly prepared silver oxide in alkali solution. The tricarboxylic acid obtained melted at Isa-189 O. and was identical with the substance obtained according to Example 1.

E'sample 5 '1. The 2-substituted rumn 3,4 dicarboxylic acids oi. the formula wherein A is a nucleus of the sroup consistins oi the iuran and tetrahydroiuran nuclei, the CQOH groups being attached in the 8,4-positions of the said nucleus, and the -(CH:)=R group being attached in the 2-position or the said nucleus, :0 being a whole positive integer, and B being a member of the class consisting of a carboxyl group and a group convertible to a carboxyl group.

2. The Z-substltuted iuran 3,4 dicarboxylic H000 COOK H000 COOK l /I (CHI)ICOOH wherein n represents a whole positive integer.

4. iuran-3.4-dicarboxy-(2) -n-valeric acid of the formula H000 COOH L J-CHr-ClIrCkCHr-C 0 0H having a melting point of 188-l89 C.

5. The 2-substltuted iuran 3,4 dicarboxylic acids or the general iormula H000 coon OKs-CH: tcmh-c O-N/ cm' 0 our-chi ifled to Congo red and heated on the steam bath (5 wherein :c is a whole positive figure.

6. The turan-3,4-dicarboxy-(2) -n-va.1eric acid 8. The z-substimted tetrahydro-iuran-3,4-dipiperidide of the formula carboxylic acids the formula nooc coon nooc coon l cal-on. 5 rCHrCHr-CHPCHr-CO- OHa o (cnmcoon Hr-C l 0 having a melting point of 131' C.

The z-subfltmlted Y 10 wherein :1: represents a whole positive integer. car y acids 1 the formula 9. The tetrahydro-furan-3A-dicarbcxy- (2) -nnooc coon valeric acid or the formula.

nooc coon (GHQ-B 0 wherein 2 represents a. whole positive integer. and o CHPCHP'CHPCHPCOOH R stands for a member of the class consisting of a carbcxyl group and a. group convertible to carboxyl. KLAUS HOFMANN. 

